Talk at RSSDI 2010 quarterly meeting, Trivandrum , 3/10/2010

1. Diabetes and Cancer
http://www.guardian.co.uk/society/2008/oct/06/health.cancer
Mathew John, MD, DM, DNB
Providence Endocrine & Diabetes Specialty Centre
Trivandrum, India
www.endocrinologydiabetes.com

2. Agenda
• Diabetes and Cancer
• Insulin, its receptor , IGF-1 and cancer pathogenesis
• Diabetes therapies and cancer
Insulin and Analogs
Metformin
Glitazones
ARB

3. Introduction
• Worldwide cancer is the 2nd and diabetes in the 12 th
common cause of death
• Cancer and diabetes are diagnosed within the same
individual more frequently than would be expected by
chance, even after adjusting for age

4. Causes of Cancer
Estimate percentage of total cancer deaths attributable to
established causes of cancer
Dileep G. Bal, M.D., Diet and Cancer

5. Diabetes and Cancer
A Metaanalysis
Vigneri et al . Endocrine-related Cancer. E pub ahead of print 2009.
Source: http://erc.endocrinology-journals.org, Accessed 4th September 2009

6. Risk factors for diabetes and
cancer
Non modifiable Modifiable
• Age • Diet
• Sex • Overweight/Obesity
• Race/Ethnicity • Physical activity
• Smoking
• Alcohol
GIOVANNUCCI E ,Diabetes and Cancer A consensus report Diabetes Care 33:1674–1685, 2010

7. Risk factors for Diabetes & Cancer
Non modifiable Modifiable
• Age • Diet
• Sex • Overweight/Obesity
• Race/Ethnicity • Physical activity
DIABETES
• Smoking
• Alcohol
CANCER
Made by data from GIOVANNUCCI E ,Diabetes and Cancer A consensus report Diabetes Care
33:1674–1685, 2010

8. Obesity and Cancer
• The cancers most consistently associated with
overweight and obesity are those of the
• Breast • Liver
• Colon/rectum
• Endometrium
• Pancreas
• Esophagus,
• Growing body of evidence suggests that weight gain is
associated with an increased risk of some cancers,
breast cancer in particular
GIOVANNUCCI E ,Diabetes and Cancer A consensus report Diabetes Care 33:1674–1685, 2010

9. Body-mass index and incidence of cancer: a
systematic review and meta-analysis
of prospective observational studies
Summary risk estimates by cancer sites in men Summary risk estimates by cancer sites in women
Lancet 2008; 371: 569–78

10. Diet and Cancer
Picture removed Picture removed
Fruits and vegetables Red meat

11. Meat and colorectal cancer
Processed meat Red meat
Sandhu MS et al. CEBP 2001;10:439- 446

12. Vegetables and Colorectal Cancer
Prospective Cohort Studies
Dileep G. Bal, M.D., Diet and Cancer

13. Whole grains & cancer
Prospective cohort studies
Dileep G. Bal, M.D., Diet and Cancer

14. Epidemiological studies of physical activity and
colon and colorectal cancer risk
Prospective studies
CM. Friedenreich Physical Activity and Cancer Prevention: From Observational to Intervention Research
Cancer Epidemiology, Biomarkers & Prevention Vol. 10, 287–301, April 2001

15. Tobacco Smoking
• Tobacco smoking accounts for
71% of all trachea, bronchus,
and lung cancer deaths
• Smoking is also an
independent risk factor for the
development of diabetes
GIOVANNUCCI E ,Diabetes and Cancer A consensus report Diabetes Care 33:1674–1685, 2010

16. Alcohol
• Moderate alcohol consumption increases the risk of
many types of cancer including those of the oral cavity,
pharynx, larynx, esophagus, liver, colon/rectum,
and female breast
• Excess alcohol consumption is also a risk factor for
diabetes
GIOVANNUCCI E ,Diabetes and Cancer A consensus report Diabetes Care 33:1674–1685, 2010

17. Diabetes & Cancer
Interpreting associations
• Many risk factors for CANCER are also risk factors for
DIABETES
• Exercise caution in interpreting associations between
DIABETES and CANCER

18. Pathogenesis of Cancer
Dileep G. Bal, M.D., Diet and Cancer

19. The link
The most plausible hypothesis linking diabetes and
diabetes therapies to cancer is via the
Insulin and IGF-1 receptor
M. Pollak, D. Russell-Jones Insulin analogues and cancer risk: cause for concern or cause ce´ le` bre?
Int J Clin Pract, April 2010, 64, 5, 628–636

20. Insulin IGF-1
• Cancer cells express
Insulin receptor isoform A
and IGF-1 receptors
Insulin IGF-1
Receptor Receptor • Insulin receptor can induce
Mitogeneis
Metabolic effects Growth effects
Glucose transport RNA & DNA synthesis
Glycogen synthesis Cell proliferation
Protein synthesis Cell survival
Insulin, IGF-1

21. Insulin receptor, IGF-1 receptors
and hybrid receptors

22. Diabetes therapies and cancer
• Insulin & Insulin Analogs
• Metformin
• Thiazolidinediones
• Secreatgogues
• GLP-1 associated agents
• Angiotensin receptor blockers

23. Differences between insulins in receptor
binding properties.
Metabolic
Insulin receptor Insulin receptor IGF-I receptor Mitogenic
Analogue potency
affinity (%) off-rate (%) affinity (%) potency (%)
(lipogenesis) (%)
Human insulin 100 100 100 100 100
B10Asp 205 ± 20 14 ± 1* 207 ± 14 287 ± 50 975 ± 173
Aspart 92 ± 6 81 ± 8* 101 ± 2 81 ± 9 58 ± 22
Lispro 84 ± 6† 100 ± 11† 82 ± 3 156 ± 16 66 ± 10
Glargine 86 ± 3 152 ± 13 60 ± 3 641 ± 51 783 ± 132
A21Gly 78 ± 10 162 ± 11 88 ± 3 42 ± 11 34 ± 12
B31B32diArg 120 ± 4 75 ± 8 75 ± 5 2049 ± 202 2180 ± 390†
Detemir 46 ± 5‡/18 ± 2§ 204 ± 9 ca 27¶ 16 ± 1§ ca 11¶
Kurtzhals P, Schäffer L, Sørensen A et al. Correlations of receptor binding and metabolic and mitogenic
potencies of insulin analogs designed for clinical use. Diabetes 2000; 49: 999–1005

24. Insulin-Receptor Interaction
Insulin/
Insulin Analog
Mitogenic potential of insulin
Insulin Increased duration at IR IGF-1
Receptor(IR) Receptor
Increased affinity at IGF-1 R
Different insulin analogs have different affinities to insulin
receptor and IGF-1 receptor

25. Other experimental data
• Pancreatic cancer cell line responded similarly to HI and
Glargine
Erbel S, Diabetes Care 2008, 31: 1105
• Colorectal, breast and prostate cell lines showed
proliferative changes and resistance to apoptosis with
Glargine, Detemir,Lispro but not Human Insulin
Weinstein D, Diabetes Metab Res Rev 25: 41-49
• Growth of malignant cell line MCF7 was strongly
promoted by insulin Glargine , but not other insulins
Shukla A, Endocr Rel Cancer 2009 16: 429
Smith U, Gale EAM Diabetologia 2009; published online July 14. DOI:10.1007/
s00125-009-1441-5.

26. A cohort study from Germany shows
dose dependent cancer risk with Lantus
(N=127031)
EASD requests investigators in Sweden, Scotland & UK
to conduct similar population based studies
Sweden Scotland UK
Significant increase in
Significant increase in
incidence of all cancers No increased risk of
incidence of Ca. Breast
in people using cancer with
in women using
Glargine monotherapy insulin analogues
Glargine monotherapy
(N=49197) (N=10067)
(N=114841)
EASD communicates possible link between glargine and cancer

27. Criticism to studies
• Observational study
• Biological implausibility : short duration 1.31 years
• Unexplained improvement of Glargine on all cause
mortality
• No difference between cancer risk in crude analysis
• Different tumors : unlikely that one agent will produce
different tumors
Smith U, Gale EAM Diabetologia 2009; published online July 14. DOI:10.1007/
s00125-009-1441-5.

28. Glargine : metaanalysis of
randomised controlled trials
• 31 studies, 12 in type 1 diabetes and 19 in type 2 diabetes.
Twenty compared insulin Glargine with NPH insulin
• Studies were generally of 6 months’ duration, except for trial
reference number 4016 (n=1,017), which had a duration of 5
years.
• Insulin Glargine was not associated with an increased incidence of
cancer, including breast cancer, compared with the comparator
group
P. D. Home & P. Lagarenne. Published online: 15 September 2009

29. Insulin glargine & malignancy :
prospective studies
Ehninger G, Schmidt AH Putting Insulin Glargine and Malignancies into Perspective
The Oncologist 2009;14:1169–1174

30. Current recommendation
FDA
FDA recommends that patients should not stop taking their insulin
therapy without consulting a physician
American Association of Clinical Endocrinologists
The AACE does not recommend that the use of any insulin be
changed.
The European Association for the Study of Diabetes(EASD)
Patients with diabetes taking Lantus should continue to do so, although
some might wish to consider alternative types of insulin
Accessed from FDA/AACE/EASD websites on 5/12/2009

31. Metformin
In laboratory models
• Inhibit cell proliferation,
• Reduce colony formation
• Partial cell cycle arrest in cancer cell lines

32. Metformin and cancer prevention
Mechanism
•Activation of AMP kinase
•Inhibits genes involved
in gluconeogenesis
•AMPK has role in tumor
suppression
Chong CR, Chabner BA. Mysterious Metformin The Oncologist 2009;14:1178–1181

33. Metformin reduces cancer risk in type 2 diabetes
Chong CR, Chabner BA. Mysterious Metformin The Oncologist 2009;14:1178–1181

34. Metformin & Cancer Mortality
•Adjusted HR of
Metformin use for cancer
mortality was 0.43 (0.23–
0.80)
•The hazard for cancer
mortality decreased by
42% for every 1-g
increase in the Metformin
dose.
Landman GWD et al. Metformin Associated With Lower Cancer Mortality in Type 2 Diabetes
ZODIAC-16 Diabetes Care. 2010 Feb;33(2):322-6.

35. Thiazoliinediones and Cancer
In vitro studies Rodent studies
• Inhibiting growth • PPAR gamma agonists
• Inducing apoptosis have tumorogenic
and cell properties
differentiation
• Inhibits invasion
They have found 33% reduction in lung cancer risk among TZD users
(RR 0.67; 95%; CI: 0.51–0.87)
Ohta K, Endo T, Haraguchi K, Hershman JM, Onaya T. J Clin Endocrinol Metab 2001;86:2170–2177
Rubenstrunk A, Hanf R, Hum DW, Fruchart JC, Staels B. Biochim Biophys Acta 2007;1771:1065–1081
Liu H, Zang C, Fenner MH. et al. PPAR gamma ligands and ATRA inhibit the invasion of human breast
cancer cells in vitro. Breast Cancer Res Treat 2003; 79: 63–74.
Govindarajan R, Ratnasinghe L, Simmons DL. et al. Thiazolidinediones and the risk of lung, prostate, and
colon cancer in patients with diabetes. J Clin Oncol 2007; 12: 1476–1481.

36. Pioglitazone and bladder tumors
• Bladder tumors were seen in male rats receiving a dose of
pioglitazone
• Ten-year, observational cohort study as well as a nested
case-control study
• No statistically significant association between any
Pioglitazone exposure and increased bladder cancer risk in
the study (HR= 1.2, 95% CI: 0.9-1.5)
• Risk of bladder cancer increased with increasing dose and
duration of Pioglitazone use, reaching statistical
significance after 24 months of exposure
http://www.fda.gov/Drugs/DrugSafety/ucm226214.htm

37. Insulin secretagogues
• Limited studies linking secreatgogue use to malignancy
• Very few cancer cases among users

38. GLP-1 associated agents
• Liraglutide increased risk of medullary thyroid cancer in
rats and mice in preclinical tests
• In transgenic rodent model, the DPP-4 inhibitor
sitagliptin was demonstrated to increase pancreatic
ductal hyperplasia
• No increase in human cancer incidence with these
agents

39. Pathogenesis of Cancer
Insulin and Analogs
Insulin is unlikely
to be Mutagenic Insulin is likely to be
mitogenic ( IR – A and
IGF1 Receptor
Dileep G. Bal, M.D., Diet and Cancer

40. ARB and Cancer
Cancer occurrence reported in all included trials of Angiotensin-receptor blockers
Sipahi I ,Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomized
controlled trials Lancet Oncol 2010; 11: 627–36

41. ARB and Cancer
• ARBs are associated with a modestly increased risk of
new cancer occurrence
• RAAS is involved in regulation of cell proliferation,
tumour growth, angiogenesis, and metastasis
• AT1R blockade with an ARB (which is associated
with unopposed AT2R stimulation) and direct stimulation
of AT2R are capable of stimulating tumour angiogenesis
in vivo.
Sipahi I ,Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomized
controlled trials Lancet Oncol 2010; 11: 627–36

42. Messages
• Diabetes, obesity and insulin resistance are independently
associated with cancer
• The association between diabetes and cancer is
confounded by different agents
•
• Insulin interaction with Insulin receptor and IGF-1
receptor forms the basis
• Insulin analogs are likely to be mitogenic (not mutagenic)

43. Thank you
www.providence.co.in: for patient information materials
twitter.com/providenceendo : for slide presentations

44. Disclaimer
The material for these slides were derived from various sources including pictures
and cartoons from the world wide web. I have tried my best to acknowledge all
possible sources and references. However, if I have overlooked any particular
reference, it is not done intentionally. Anyone reproducing materials from this
presentations should acknowledge the author of the original work. The case given is
imaginary and is given only to support the purpose of this talk. Any similarity to
published case report/ patient is unintentional.